rs199422290

Positions:

• chr5-1294877-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000310581.10(TERT):​c.112del​(p.Leu38TrpfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. L38L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TERT ENST00000310581.10 frameshift
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.98

Genes affected

TERT (HGNC:11730): (telomerase reverse transcriptase) Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.112del	p.Leu38TrpfsTer40	frameshift_variant	1/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.112del	p.Leu38TrpfsTer40	frameshift_variant	1/15		NP_001180305.1
TERT	NR_149162.3	n.191del		non_coding_transcript_exon_variant	1/13
TERT	NR_149163.3	n.191del		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.112del	p.Leu38TrpfsTer40	frameshift_variant	1/16	1	NM_198253.3	ENSP00000309572	P2
TERT	ENST00000334602.10	c.112del	p.Leu38TrpfsTer40	frameshift_variant	1/15	1		ENSP00000334346	A2
TERT	ENST00000460137.6	c.112del	p.Leu38TrpfsTer40	frameshift_variant, NMD_transcript_variant	1/13	1		ENSP00000425003
TERT	ENST00000656021.1	c.112del	p.Leu38TrpfsTer40	frameshift_variant, NMD_transcript_variant	1/17			ENSP00000499759

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Interstitial lung disease 2 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199422290; hg19: chr5-1294992;